US12186366B2 - Clusterin for use in the treatment of thrombotic microangiopathies - Google Patents

Clusterin for use in the treatment of thrombotic microangiopathies Download PDF

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US12186366B2
US12186366B2 US16/632,684 US201816632684A US12186366B2 US 12186366 B2 US12186366 B2 US 12186366B2 US 201816632684 A US201816632684 A US 201816632684A US 12186366 B2 US12186366 B2 US 12186366B2
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clusterin
tma
treatment
hus
patient
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US20200138902A1 (en
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Jean-Francois Augusto
Cecile Contin-Bordes
Yahsou Delmas
Patrick Blanco
Yves Delneste
Pascale Jeannin
Celine Beauvillain
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Centre National de la Recherche Scientifique CNRS
Universite dAngers
Institut National de la Sante et de la Recherche Medicale INSERM
Centre Hospitalier Universitaire de Bordeaux
Universite de Bordeaux
Centre Hospitalier Universitaire dAngers
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Centre National de la Recherche Scientifique CNRS
Universite dAngers
Institut National de la Sante et de la Recherche Medicale INSERM
Centre Hospitalier Universitaire de Bordeaux
Universite de Bordeaux
Centre Hospitalier Universitaire dAngers
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Assigned to CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE, INSERM - INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE, CENTRE HOSPITALIER UNIVERSITAIRE DE BORDEAUX, CENTRE HOSPITALIER UNIVERSITAIRE D'ANGERS, Universite de Bordeaux, UNIVERSITE D'ANGERS reassignment CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BLANCO, PATRICK, DELMAS, Yahsou, AUGUSTO, JEAN-FRANCOIS, BEAUVILLAIN, CELINE, DELNESTE, YVES, JEANNIN, PASCALE, CONTIN-BORDES, CECILE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/22—Haematology
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/22—Haematology
    • G01N2800/226—Thrombotic disorders, i.e. thrombo-embolism irrespective of location/organ involved, e.g. renal vein thrombosis, venous thrombosis

Definitions

  • the present invention relates to the use of a protein for use in the treatment of thrombotic microangiopathies, and also to an ex vivo method for stratification of a patient who is or may be suffering from TMA.
  • TMA thrombotic microangiopathy
  • TTP The number of new cases of TTP is from 5 to 10 cases per million inhabitants and per year. HUS frequency is also very close to these values.
  • TMAs include, in addition to these most conventional forms, HELLP syndrome, which is a serious complication or a variant of pre-eclampsia in pregnant women, characterized by hemolysis, elevated liver enzymes and a low platelet count. Secondary forms of TMA also exist which occur in a specific context such as, for example, during certain treatments, during chemotherapy, during cancer or during a bone marrow allograft.
  • the treatment comprises medicaments capable of blocking the complement proteins responsible for the disease.
  • Eculizumab is currently the only treatment authorized in the atypical HUS indication. This treatment is extremely expensive since a bottle of 300 mg of Eculizumab costs more than 4000 euros and, as maintenance treatment, the dosage regimen is 1200 mg per 14 days.
  • clusterin binds to histones and that it inhibits the inflammatory and cytotoxic action thereof.
  • clusterin binds to histones, which are danger molecules with a central role in TMAs. They have also shown that clusterin neutralizes the actions of histones, firstly by blocking the production of pro-inflammatory molecules, in particular of pro-inflammatory cytokines such as IL-6 and TNF ⁇ , by human monocytes, and secondly by blocking the induction of endothelial cell death, in particular by neutralizing the capacity of histones to induce endothelial cell death. The inventors have also shown that the addition of clusterin to sera from patients containing histones decreases their toxicity with respect to endothelial cells.
  • the inventors have shown that the amount of clusterin correlates with the state of health of patients suffering from TMA. They have in fact been able to demonstrate that serum clusterin levels are lower in patients suffering from TMA at diagnosis than in healthy subjects.
  • the invention could facilitate the treatment of TMAs for which the current treatments depend on the etiology.
  • the use of clusterin could thus be proposed to any patient with TMA regardless of the etiology, allowing a faster treatment that is not dependent on the etiological diagnosis.
  • a first subject relates to clusterin for use thereof in the treatment of thrombotic microangiopathies.
  • Clusterin also known as apolipoprotein J, is an 80 kDa soluble heterodimeric glycoprotein bonded by disulfide bridges, which is strongly conserved during evolution and among mammals. Clusterin is abundant in physiological fluids (at concentrations ranging from 100 to 300 ⁇ g/ml in human serum by way of example) and is induced in response to a large variety of cell and tissue lesions. It is known that clusterin has a chaperone activity and is a functional homolog of the intracellular small heat shock proteins (HSPs). It binds to the hydrophobic domains of non-native proteins and targets them for receptor-mediated internalization and intracellular lysosomal degradation. This function allows clusterin to interact with a wide spectrum of molecules, such as lipids, complement system components, amyloid plaque-forming proteins, and immunoglobulins.
  • HSPs small heat shock proteins
  • clusterin has its general meaning, and denotes a glycoprotein as described above.
  • the clusterin may be an animal clusterin or a human clusterin. It may be a clusterin chosen from the group comprising a plasma clusterin, a recombinant clusterin and a synthetic clusterin.
  • Plasma clusterin can be obtained by purification from plasma, in particular human plasma, by any purification method known to those skilled in the art, for example by means of immunoaffinity, of cation exchange, of plasma fractionation and/or of size exclusion chromatography.
  • Recombinant clusterin can be obtained by standard recombinant DNA techniques, well known to those skilled in the art.
  • a gene encoding a clusterin can be introduced by means of a vector into the genome of a producer species, such as a bacterium, a mammalian cell in culture or a transgenic animal.
  • the vectors which allow the introduction, maintenance and expression of genes in a host cell are known to those skilled in the art. Generally, they have sequences essential to the expression of the gene introduced, such as promoter sequences, polyadenylation sequences and selectable genes.
  • Such vectors can be chosen from the ones known to those skilled in the art, for example from adenoviruses, retroviruses, plasmids or bacteriophages, this list not being limiting.
  • Any mammalian cell can be used as host cell, that is to say as cell expressing the gene encoding clusterin, for example CHO, CHO dhfr ⁇ (for example CHO DX BII, CHO DG44), CHO Lec13, YB2/0, SP2/0, NSO, 293, BHK, Jurkat, Vero or COS.
  • Synthetic clusterin can be obtained by any known method of de novo protein design other than that used to prepare recombinant protein, such as for example by assembly on a matrix.
  • the clusterin sequences from numerous species are known and can be used in the context of the invention.
  • the amino acid sequence of clusterin may be that of the sequence SEQ ID No.: 1.
  • the clusterin used may be a variant having at least 70% identity with the sequence SEQ ID No.: 1, for example 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% or 100% identity with the sequence SEQ ID No.: 1.
  • the sequence identity can be determined by means of any suitable technique known to those skilled in the art, for example by means of a sequence alignment algorithm such as BLAST P.
  • a clusterin variant may be a variant of which the function is conserved.
  • it may be a clusterin in which a given amino acid residue in natural clusterin is modified in the variant without impairing either the conformation or the overall function of the clusterin, including, but not being limited to, the replacement of an amino acid with an amino acid having similar properties, such as for example the polarity, the hydrogen-bonding potential, the hydrophobicity, the acidity, the basicity, the aromaticity, etc. Consequently, a variant also denotes a polypeptide which has at least 70% amino acid identity and which has the same properties or functions that are identical or substantially similar to the native or parental protein to which it is compared.
  • clusterin is linked to the chaperone function of the histones of said clusterin.
  • histone has its general meaning. Histones are small basic proteins with a high lysine or arginine content, the function of which is in DNA packaging. Histones are highly conserved and can be grouped together in five major classes: H1/H5, H2A, H2B, H3 and H4 organized in two super-classes of core histones (H2A, H2B, H3 and H4) and linker histones (H1 and H5).
  • a histone protein may be a full-length histone, a fragment or a variant thereof.
  • a histone variant may be modified for example by amino acid deletion, addition and/or substitution.
  • a histone may be modified by acetylation and/or methylation of the lysine and of the arginine.
  • the modifications do not substantially compromise the polycationic nature of the histone or the capacity of the histone to localize in an organ.
  • clusterin binds to histones so as to inhibit all or part of the inflammatory and/or toxic action thereof. It may involve an inhibition of at least 20%, for example 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%, or 100%, of the inflammatory and/or toxic action of histones.
  • the treatment can be carried out by administration of a therapeutically effective dose of clusterin, which is a minimum dose that makes it possible to confer the therapeutic benefit on a patient. It may be a dose determined by the physician according to the pathological condition, the stage of the pathological condition, the initial assay of the amount of clusterin of the patient, and/or the patient.
  • the daily clusterin dose may be between 0.01 and 1000 mg per adult per day. It may for example be a daily dose of 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 or 500 mg of clusterin.
  • the dosage may be adjusted according to the stage of treatment, for example it may be increased or decreased during treatment depending on the observations of the physician.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US16/632,684 2017-07-21 2018-07-20 Clusterin for use in the treatment of thrombotic microangiopathies Active 2038-10-28 US12186366B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR1756912 2017-07-21
FR1756912A FR3069156B1 (fr) 2017-07-21 2017-07-21 Clusterine pour son utilisation dans le traitement des micro-angiopathies thrombotiques
PCT/FR2018/051854 WO2019016485A1 (fr) 2017-07-21 2018-07-20 Clusterine pour son utilisation dans le traitement des micro-angiopathies thrombotiques

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EP (1) EP3655014B1 (fr)
JP (1) JP7358695B2 (fr)
AU (1) AU2018303280B2 (fr)
CA (1) CA3065633A1 (fr)
DK (1) DK3655014T3 (fr)
ES (1) ES2883952T3 (fr)
FR (1) FR3069156B1 (fr)
WO (1) WO2019016485A1 (fr)

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CN112210003A (zh) * 2019-07-09 2021-01-12 厦门德馨尚品医疗科技有限公司 一种重组载脂蛋白j及其类似物的晶体结构及应用

Citations (7)

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Publication number Priority date Publication date Assignee Title
WO2001066689A2 (fr) * 2000-03-07 2001-09-13 Hyseq, Inc. Nouveaux acides nucleiques et polypeptides
WO2002022635A1 (fr) * 2000-09-11 2002-03-21 Isis Pharmaceuticals, Inc. Modulation antisens de l'expression de la clusterine
WO2002042441A2 (fr) 2000-11-22 2002-05-30 Baxter Aktiengesellschaft Polypeptide de la protease de clivage du facteur de von willebrand (vwf), acide nucleique codant ce polypeptide et utilisation de ce polypeptide
WO2013188686A2 (fr) 2012-06-15 2013-12-19 Wayne State University Biomarqueurs utilisés pour prédire ou détecter précocement la pré‑éclampsie et/ou le syndrome de hellp
WO2014035876A1 (fr) 2012-08-27 2014-03-06 William Marsh Rice University Compositions de facteurs b du complément désactivé à la chaleur et procédé
US20150079613A1 (en) * 2013-08-07 2015-03-19 Ryan Kitchel Atypical hemolytic uremic syndrome biomarker proteins
WO2016176565A1 (fr) 2015-04-30 2016-11-03 Idexx Laboratories, Inc. Détection spécifique d'isoformes de la clusterine

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001066689A2 (fr) * 2000-03-07 2001-09-13 Hyseq, Inc. Nouveaux acides nucleiques et polypeptides
WO2002022635A1 (fr) * 2000-09-11 2002-03-21 Isis Pharmaceuticals, Inc. Modulation antisens de l'expression de la clusterine
WO2002042441A2 (fr) 2000-11-22 2002-05-30 Baxter Aktiengesellschaft Polypeptide de la protease de clivage du facteur de von willebrand (vwf), acide nucleique codant ce polypeptide et utilisation de ce polypeptide
WO2013188686A2 (fr) 2012-06-15 2013-12-19 Wayne State University Biomarqueurs utilisés pour prédire ou détecter précocement la pré‑éclampsie et/ou le syndrome de hellp
WO2014035876A1 (fr) 2012-08-27 2014-03-06 William Marsh Rice University Compositions de facteurs b du complément désactivé à la chaleur et procédé
US20150079613A1 (en) * 2013-08-07 2015-03-19 Ryan Kitchel Atypical hemolytic uremic syndrome biomarker proteins
WO2016176565A1 (fr) 2015-04-30 2016-11-03 Idexx Laboratories, Inc. Détection spécifique d'isoformes de la clusterine

Non-Patent Citations (12)

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Title
Benz et al.; "Thrombotic microangiopathy: new insights"; Current Opinion in Nephrology and Hypertension, vol. 19, Issue No. 3; 2010; pp. 242-247.
Clusterin preproprotein [Homo sapiens]. NP_001822.3 https://www.ncbi.nlm.nih.gov/protein/NP_001822.3 download [Aug. 14, 2020 3:50 :34 PM] (Year: 2020). *
Cofiell et al.; "Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS"; Blood, vol. 125, Issue No. 21; 2015; pp. 3253-3262.
Craggs et al.; "Clusterin/Apolipoprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases"; Neuropathology and Applied Neurobiology, vol. 42, Issue No. 2; 2016; pp. 194-209.
Cunin et al. Clusterin facilitates apoptotic cell clearance and prevents apoptotic cell-induced autoimmune responses. Cell Death and Disease (2016) 7, e2215. (Year: 2016). *
Cunin et al.; "Clusterin facilitates apoptotic cell clearance and prevents apoptotic cell-induced autoimmune responses"; Cell Death and Disease, vol. 7, Issue No. 5; 2016; e2215 doi:10.1038/cddis.2016.113.
Dabbs RA, Wilson MR (2014) Expression and Purification of Chaperone-Active Recombinant Clusterin. PLoS One. Jan. 23, 2014; 9(1): e86989. (Year: 2014). *
Fuchs et al. Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies. Blood (2012) 120 (6): 1157-1164. (Year: 2012). *
International Search Report and Written Opinion for International Application No. PCT/FR2018/051854; International Filing Date: Jul. 20, 2018; Date of Mailing: Oct. 23, 2018; 12 pages.
Kazue; "Terminal complement complex (TCC) levels in urine in patients with renal diseases"; The Hokkaido Journal of Medical Science, vol. 76, Issue No. 2; 2001; pp. 71-84.
Lankford et al.; "Thrombotic Thrombocytopeniarpura: New Insights in Disease Pathogenesis and Therapy"; Transfusion Medicine Reviews, vol. 14, Issue No. 3; 2000; pp. 244-257.
Stahl et al. A novel mutation in the complement regulator clusterin in recurrent hemolytic uremic syndrome. Molecular Immunology 46 (2009) 2236-2243. (Year: 2009). *

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Publication number Publication date
EP3655014A1 (fr) 2020-05-27
CA3065633A1 (fr) 2019-01-24
AU2018303280B2 (en) 2025-01-16
WO2019016485A1 (fr) 2019-01-24
US20200138902A1 (en) 2020-05-07
DK3655014T3 (da) 2021-08-23
JP7358695B2 (ja) 2023-10-11
AU2018303280A1 (en) 2020-01-30
FR3069156B1 (fr) 2019-08-09
FR3069156A1 (fr) 2019-01-25
JP2020530484A (ja) 2020-10-22
ES2883952T3 (es) 2021-12-09
EP3655014B1 (fr) 2021-06-16

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